RESEARCH ARTICLE Evolution and Emergence of Enteroviruses through Intra- and Inter-species Recombination: Plasticity and Phenotypic Impact of Modular Genetic Exchanges in the 5 ’ Untranslated Region

Genetic recombination shapes the diversity of RNA viruses, including enteroviruses (EVs), which frequently have mosaic genomes. Pathogenic circulating vaccine-derived poliovirus (cVDPV) genomes consist of mutated vaccine poliovirus (PV) sequences encoding capsid proteins, and sequences encoding nonstructural proteins derived from other species ’ C EVs, including certain coxsackieviruses A (CV-A) in particular. Many cVDPV genomes also have an exogenous 5 ’ untranslated region (5 ’ UTR). This region is involved in virulence and includes the cloverleaf (CL) and the internal ribosomal entry site, which play major roles in replication and the initiation of translation, respectively. We investigated the plasticity of the PV genome in terms of recombination in the 5 ’ UTR, by developing an experimental model involving the rescue of a bipartite PV/CV-A cVDPV genome rendered defective by muta-tions in the CL, following the co-transfection of cells with 5 ’ UTR RNAs from each of the four human EV species (EV-A to-D). The defective cVDPV was rescued by recombination with 5 ’ UTR sequences from the four EV species. Homologous and nonhomologous recombi-nants with large deletions or insertions in three hotspots were isolated, revealing a strikin